Abstract In humans, mechanical hypersensitivity is characterized by sensitivity to simple movements and is described as shooting and stabbing pain;it is a hallmark of many inflammatory and neuropathic pain conditions. The prostaglandin D2 metabolite, 15-deoxy- 12,14-prostaglandin J2 (15d-PGJ2), is best characterized as an anti-inflammatory prostaglandin. Recently we showed 15d-PGJ2 activates thermoTRP ion channel TRPA1 in heterologous expression systems and in dorsal root ganglion (DRG) neurons, inducing nociceptive behavior in mice via a TRPA1-dependent mechanism. Here we report that 15d-PGJ2 is also a peripherally acting anti- nociceptive compound, attenuating hypersensitivity to mechanical stimuli in several pain models. We hypothesize that the mechanism of 15d-PGJ2 attenuation of mechanical hypersensitivity is via initial activation followed by desensitization of TRPA1 channels. We will test this hypothesis by utilizing behavioral, molecular and electrophysiological tools. Our studies lay the foundation for future work in which we will explore the efficacy of 15d-PGJ2 as a peripherally acting pain therapeutic. PUBLIC HEALTH RELEVANCE: The Transient Receptor Potential ion channel TRPA1 is a proposed cold- and mechanically-gated channel that is also activated by a variety of irritants, inflammatory mediators and products of cellular stress. Animal studies demonstrate that TRPA1 plays a role in acute pain signaling as well as inflammation- and neuropathic injury- induced hypersensitivity. In this proposal we have identified an endogenous anti-inflammatory compound that reduces mechanical hypersensitivity in several pain models and we propose a TRPA1-dependent mechanism. We will demonstrate the analgesic action and specificity of this compound by completing a panel of behavioral tests and cellular studies. Our studies will contribute to the future development of TRPA1-targeted pain therapeutics.